Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.

Background-Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE)and peroxisome proliferator-activated receptor-␥ in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE Ϫ/Ϫ ) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-␥ agonist (eg, rosiglitazone). Methods and Results-We report that apoEϪ/Ϫ mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE Ϫ/Ϫ were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE Ϫ/Ϫ mice were insulin resistant and had more severe PAH than female apoE Ϫ/Ϫ mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE Ϫ/Ϫ mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE Ϫ/Ϫ or C57Bl/6 control mice. Conclusions-We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-␥ activation can reverse PAH in an animal model. Key Words: apolipoproteins Ⅲ glucose Ⅲ hypercholesterolemia Ⅲ hypertension, pulmonary Ⅲ insulin Ⅲ metabolism Ⅲ PPAR gamma A lthough insulin resistance is associated with systemic cardiovascular disease, 1-3 it has not been implicated as a predisposing factor in pulmonary arterial hypertension (PAH). Several findings, however, support such an association. Patients with idiopathic PAH have reduced pulmonary mRNA expression of peroxisome proliferator-activated receptor gamma (PPAR␥), 4 a ligand-activated nuclear receptor and transcription factor that regulates adipogenesis and glucose metabolism. [5][6][7] They also have reduced pulmonary mRNA expression of apolipoprotein E (apoE), 8 a protective factor known to reduce circulating oxidized low-density lipoprotein and atherogenesis in the vessel wall. 9 Deficiency of both PPAR␥ and apoE has been linked to insulin resistance and the metabolic syndrome. 7,9 Elevated levels of several circulating factors that are normally repressed by PPAR␥ are associated with insulin resistance 3 and implicated in the pathobiology of PAH. These include interleukin-6, 10,11 fractalkine, 12,13 monocyte chemoattractant protein-1, 14 endothelin-1 (ET-1), [15][16][17] and the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADM...

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Human embryonic stem cells (hESCs) can serve as a potentially limitless source of cells that may enable regeneration of diseased tissue and organs. Here we investigate the use of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in promoting recovery from cardiac ischemia reperfusion injury in a mouse model. Using microarrays, we have described the hESC-CM transcriptome within the spectrum of changes that occur between undifferentiated hESCs and fetal heart cells. The hESC-CMs expressed cardiomyocyte genes at levels similar to those found in 20-week fetal heart cells, making this population a good source of potential replacement cells in vivo. Echocardiographic studies showed significant improvement in heart function by 8 weeks after transplantation. Finally, we demonstrate long-term engraftment of hESC-CMs by using molecular imaging to track cellular localization, survival, and proliferation in vivo. Taken together, global gene expression profiling of hESC differentiation enables a systems-based analysis of the biological processes, networks, and genes that drive hESC fate decisions, and studies such as this will serve as the foundation for future clinical applications of stem cell therapies.

BackgroundSustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic.Methods and FindingsWe studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response.ConclusionsWe have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.